Abstract
RationaleMethamphetamine (METH) exposure is associated with damage to central monoamine systems, particularly dopamine signaling. Rodent models of such damage have revealed a decrease in the amplitude of phasic dopamine signals and significant striatal dysfunction, including changes in the molecular, system, and behavioral functions of the striatum. Dopamine signaling through D1 receptors promotes corticostriatal long-term potentiation (LTP), a critical substrate of these striatal functions.ObjectivesTherefore, the purpose of this study was to determine if METH-induced dopamine neurotoxicity would impair D1 receptor-dependent striatal LTP in mice.MethodsMice were treated with a METH binge regimen (4 × 10 mg/kg d,l-methamphetamine, s.c.) that recapitulates all of the known METH-induced neurotoxic effects observed in humans, including dopamine toxicity. Three weeks later, acute brain slices containing either the dorsomedial striatum (DMS) or dorsolateral striatum (DLS) were prepared, and plasticity was assessed using white matter, high-frequency stimulation (HFS), and striatal extracellular electrophysiology.ResultsUnder these conditions, LTP was induced in brain slices containing the DMS from saline-pretreated mice, but not mice with METH-induced neurotoxicity. Furthermore, the LTP observed in DMS slices from saline-pretreated mice was blocked by the dopamine D1 receptor antagonist SCH23390, indicating that this LTP is dopamine D1 receptor-dependent. Finally, acute in vivo treatment of METH-pretreated mice with bupropion (50 mg/kg, i.p.) promoted LTP in DMS slices.ConclusionsTogether, these studies demonstrate that METH-induced neurotoxicity impairs dopamine D1 receptor-dependent LTP within the DMS and that the FDA-approved drug bupropion restores induction of striatal LTP in mice with METH-induced dopamine neurotoxicity.
Highlights
Methamphetamine (METH) is a highly addictive psychostimulant with negative health, social, and economic consequences
Densitometric analysis of dopamine transporter (DAT) immunohistochemistry within the dorsomedial striatum (DMS) and dorsolateral striatum (DLS) was used to confirm dopamine neurotoxicity resulting from the METH binge regimen
In the bupropion long-term potentiation (LTP) experiments where only METH-pretreated groups were used, a one-way ANOVA revealed that there was not a significant difference in DAT expression between groups (DMS: F(2, 28) = 1.173, p = 0.3241, data not shown; DLS: F(2, 23) = 0.6379, p = 0.5375, data not shown), indicating that all METH-pretreated groups used during the bupropion LTP experiment had similar levels of dopamine neurotoxicity
Summary
Methamphetamine (METH) is a highly addictive psychostimulant with negative health, social, and economic consequences. Treatments for METH use disorder are currently limited to behavioral therapies that are generally unsuccessful. The National Institute on Drug Abuse has declared research to identify medications to treat METH use disorder a priority (NIDA 2020). Cognitive deficits are apparent in individuals with a history of METH abuse, and targeting cognitive function may be an efficacious approach to managing METH use disorder. To target cognitive dysfunction associated with METH use and to establish more successful treatments for METH use disorder, the neurotoxic effects of METH must be better understood. The striatum is critically involved in cognitive processes such as learning, motivation, and behavioral flexibility, and striatal dysfunction can have significant cognitive and behavioral consequences. Studies using a METH binge regimen to model the long-term effects of METH-induced neurotoxicity report lasting changes to molecular, system, and behavioral functions of the striatum.
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